Venereal syphilis is a chronic inflammatory disorder driven by the persistence of its etiologic agent Treponema pallidum. Though the immune/inflammatory response at sites of local treponemal infection may ultimately underlie the development of both protective immunity and clinical manifestations, these local cellular processes have yet to be characterized in humans using the tools of contemporary cellular and molecular immunology. The components of T. pallidum that induce these potentially deleterious inflammatory processes also remain poorly characterized. Our understanding of cellular immunity in syphilis is further compromised by our currently limited knowledge concerning the interactions between syphilis and HIV infection. Accordingly, the proposed research has three Specific Aims. In Specific Aim 1, we will perform immunocytochemical analysis of skin biopsies and flow cytometry analysis of leukocytes in suction blisters to characterize cutaneous cellular immune processes in HIV- and HIV+ patients with secondary syphilis. Data from these studies will be correlated with our in vitro research involving immune effector cell activation by T. pallidum and treponemal lipoproteins. In Specific Aim 2, we will use the same immunocytochemical and flow cytometric approaches to characterize the cutaneous inflammatory response to synthetic analogs (lipopeptides) of T. pallidum lipoproteins. These experiments are an outgrowth of our hypothesis that T. pallidum lipoproteins are major inflammatory mediators during syphilitic infection. Building upon our observation that T. pallidum lipoprotein analogs induce HIV gene expression in vitro, the experiments in Specific Aim 3 will elucidate the mechanisms which underlie this phenomenon. A principal long-term objective of this research is to elucidate the immune/inflammatory events during syphilitic infection which engender both clinical manifestations and protective immunity. An equally important objective is to obtain cellular and molecular data which will complement our emerging understanding of the interactions between syphilis and HIV infection, including the potential for syphilis to serve as a co-factor for HIV transmission and for HIV infection to alter the clinical course of syphilis.